A Phase II Trial of Osimertinib (AZD9291) With or Without Bevacizumab in Patients With EGFR Mutation Positive NSCLC and Brain Metastases
概览
- 阶段
- 2 期
- 干预措施
- Bevacizumab
- 疾病 / 适应症
- Metastatic Lung Non-Small Cell Carcinoma
- 发起方
- National Cancer Institute (NCI)
- 入组人数
- 5
- 试验地点
- 18
- 主要终点
- Progression Free Survival (PFS)
- 状态
- 进行中（未招募）
- 最后更新
- 4天前
概览
简要总结
This phase II trial studies how well osimertinib with or without bevacizumab works in treating patients with EGFR positive non-small cell lung cancer that has spread to the brain (brain metastases). Osimertinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Bevacizumab may stop or slow non-small cell lung cancer by blocking the growth of new blood vessels necessary for tumor growth. Giving osimertinib with or without bevacizumab may work better in treating patients with non-small cell lung cancer.
详细描述
PRIMARY OBJECTIVE: I. To determine the progression-free survival with osimertinib (AZD9291) plus bevacizumab compared to osimertinib (AZD9291) alone. SECONDARY OBJECTIVES: I. To assess the safety and tolerability of the combination of osimertinib (AZD9291) and bevacizumab. II. To evaluate the time to progression in the central nervous system (CNS) with osimertinib (AZD9291) plus bevacizumab versus single-agent osimertinib (AZD9291). III. To determine the overall response rate and the intracranial response rate to the combination versus single agent. IV. To assess the overall survival in patients receiving osimertinib (AZD9291) plus bevacizumab compared to osimertinib (AZD9291) alone. TRANSLATIONAL OBJECTIVES: I. To investigate mechanisms of sensitivity and resistance to combination osimertinib (AZD9291) plus bevacizumab versus osimertinib (AZD9291) by molecularly characterizing tumor samples including T790M status. II. To assess whether circulating tumor deoxyribonucleic acid (DNA) in plasma can be used as an indicator of sensitivity and resistance to treatment. III. To determine whether an angiogenic signature using a multiplex panel array is associated with benefit from the combination of osimertinib (AZD9291) plus bevacizumab. IV. To investigate angiogenesis, immune and signaling pathway markers in tumor samples to determine biomarkers predictive of benefit from combination therapy. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients receive osimertinib orally (PO) once daily (QD) on days 1-21 and bevacizumab intravenously (IV) over 30-90 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive osimertinib PO QD on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography (CT) scan, magnetic resonance imaging (MRI), tumor biopsy and blood sample collection throughout the study. After completion of study treatment, patients are followed up for a minimum of 4 weeks.
研究者
入排标准
入选标准
- •Non-small cell lung cancer (NSCLC) with an activating EGFR mutation (exon 19 deletion, L858R point mutation, or any other mutation known to be associated with EGFR TKI sensitivity); presence of an activating EGFR mutation may be documented in tumor tissue or by plasma testing if performed in a Clinical Laboratory Improvement Act (CLIA)-certified laboratory
- •No prior treatment with an EGFR TKI; patient may have received prior chemotherapy for early-stage or advanced disease but this is not required; prior immunotherapy is not allowed
- •Patients must have at least one measurable CNS lesion that is asymptomatic, untreated, and does not require local therapy at the time of enrollment; measurable CNS disease is defined as a brain metastasis that can be accurately measured in at least one dimension (longest diameter to be recorded) as \>= 5 mm (\>= 0.5 cm) with brain magnetic resonance imaging (MRI); if the lesion is 5-10 mm in size and is the only measurable disease, MRI imaging must be performed with 1.5 mm slice thickness or less; a history of previously treated brain metastases is allowed, however any lesion present at the time of whole brain radiotherapy or included in the stereotactic radiotherapy field (or within 2 mm of the treated lesion) will NOT be considered "untreated" unless it is new or documented to have progressed unequivocally since treatment
- •Patients are not required to have measurable systemic (i.e. non-CNS) disease; if present, measurable systemic disease must be able to be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as \>= 20 mm (\>= 2 cm) with conventional techniques or as \>= 10 mm (\>= 1 cm) with spiral computed tomography (CT) scan, MRI, or calipers by clinical exam
- •Age \>= 18 years
- •Eastern Cooperative Oncology Group (ECOG) performance status =\< 2
- •Life expectancy of greater than 3 months
- •The use of anti-convulsants is allowed, as long as the patient is on a stable dose with no seizure activity for at least 2 weeks prior to initiating trial therapy
- •Female subjects should be using highly effective contraceptive measures, and must have a negative pregnancy test and not be breast-feeding prior to start of dosing if of child- bearing potential or must have evidence of non-child-bearing potential by fulfilling one of the following criteria at screening:
- •Post-menopausal defined as aged more than 50 years and amenorrheic for at least 12 months following cessation of all exogenous hormonal treatments
排除标准
- •Symptomatic brain metastases or symptomatic leptomeningeal disease; asymptomatic leptomeningeal disease is allowed
- •Patients with brain metastases for whom complete surgical resection is clinically appropriate
- •Prior treatment with any EGFR TKI
- •Prior treatment with agents targeting the VEGF pathway, including bevacizumab
- •The use of corticosteroids to control cerebral edema or treat neurologic symptoms will not be allowed, and patients who previously required corticosteroids for symptom control must be off steroids for at least 3 days without recurrence of symptoms prior to starting trial therapy; corticosteroids for other indications is allowed
- •Patients may not be receiving any other investigational agents and may not have participated in a study of an investigational agent or using an investigational device within five half-lives of the compound or 3 months, whichever is greater
- •Any unresolved toxicities from prior therapy greater than Common Terminology Criteria for Adverse Events (CTCAE) grade 1 at the time of starting study treatment with the exception of alopecia and grade 2 platinum-therapy related neuropathy
- •Concurrent, active malignancies in addition to that being studied (other than cutaneous squamous cell carcinoma or basal cell carcinoma)
- •Any contraindication to MRI (i.e. patients with pacemakers or other metal implanted medical devices)
- •Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease
研究组 & 干预措施
Arm I (osimertinib, bevacizumab)
Patients receive osimertinib PO QD on days 1-21 and bevacizumab IV over 30-90 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI, tumor biopsy and blood sample collection throughout the study.
干预措施: Bevacizumab
Arm I (osimertinib, bevacizumab)
Patients receive osimertinib PO QD on days 1-21 and bevacizumab IV over 30-90 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI, tumor biopsy and blood sample collection throughout the study.
干预措施: Biopsy Procedure
Arm I (osimertinib, bevacizumab)
Patients receive osimertinib PO QD on days 1-21 and bevacizumab IV over 30-90 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI, tumor biopsy and blood sample collection throughout the study.
干预措施: Biospecimen Collection
Arm I (osimertinib, bevacizumab)
Patients receive osimertinib PO QD on days 1-21 and bevacizumab IV over 30-90 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI, tumor biopsy and blood sample collection throughout the study.
干预措施: Computed Tomography
Arm I (osimertinib, bevacizumab)
Patients receive osimertinib PO QD on days 1-21 and bevacizumab IV over 30-90 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI, tumor biopsy and blood sample collection throughout the study.
干预措施: Osimertinib
Arm I (osimertinib, bevacizumab)
Patients receive osimertinib PO QD on days 1-21 and bevacizumab IV over 30-90 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI, tumor biopsy and blood sample collection throughout the study.
干预措施: Magnetic Resonance Imaging
Arm II (osimertinib)
Patients receive osimertinib PO QD on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI, tumor biopsy and blood sample collection throughout the study.
干预措施: Osimertinib
结局指标
主要结局
Progression Free Survival (PFS)
时间窗: From start of treatment to time of progression (in CNS or non-CNS disease) or death, whichever occurs first, assessed up to 63.7 months
The two study arms will be compared for PFS with Kaplan-Meier estimates and log-rank tests. The Rothman confidence interval (CI) will be reported. In addition, the possible risk factors will be compared for survival with log-rank test. For multivariate analysis, the proportional hazards Cox model will be applied to investigate potential prognostic factors, such as age and stage of disease of the PFS data. The adjusted p-values of the hazard ratios and the adjusted 95% confidence interval will be reported. Upon results entry, median PFS and range is provided due to study closure and early termination.
次要结局
- Overall Survival (OS)(From start of treatment to death, assessed up to 5.5 years)
- Incidence of Adverse Events(Up to 5.5 years)
- Overall Response Rate(Up to 5.5 years)
- Intracranial Response Rate(Up to 5.5 years)
- Time to Intracranial Progression(Up to 5.5 years)
- Time to Central Nervous System (CNS) Progression(From start of treatment to time of progression in the CNS, assessed up to 5.5 years)
- Objective Response Defined as a Complete or Partial Response(Up to 5.5 years)